The effect of Btk inhibition on platelet activation by GPVI and CLEC-2

Nicolson, Phillip Lindsay Ross ORCID: 0000-0002-4843-2975 (2019). The effect of Btk inhibition on platelet activation by GPVI and CLEC-2. University of Birmingham. Ph.D.

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Abstract

Background: The novel Btk inhibitor ibrutinib has recently been introduced into the clinic for treatment of lymphoproliferative disorders (LPDs) where it is unexpectedly associated with major bleeding. It has been shown to block GPVI and CLEC-2-mediated platelet function with the former correlating with bleeding. This contrasts with patients who are deficient in GPVI or Btk who experience minor/no bleeding respectively. Mice that lack CLEC-2 also have no bleeding diathesis but are protected from thromboinflammation.

Aims: This study aims to investigate the discrepancy between the bleeding seen with ibrutinib and those that lack Btk. It also aims to examine whether ibrutinib can block CLEC-2 signalling in mouse and human venous thrombosis.

Results: Ibrutinib blocks GPVI signalling due to off-target effects which occur because of the high clinical doses that are used. It blocks CLEC-2 signalling at ~50-fold lower concentrations and reduces venous thrombosis rates in patients taking it for LPD.

Conclusions: Lowering the dose of ibrutinib or developing a more specific Btk inhibitor would ameliorate the major bleeding that is seen with ibrutinib. Btk inhibitors are suitable for further study as inhibitors of CLEC-2 signalling in human venous thrombosis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):